Lupine hydrazinium compounds



2,946,798 HYDRAZINIUM coMrot-mns Bernard Rudner, Pittsburgh, Pa., assignor to W. R. Grace & 0., New York, N.Y., a corporation of Connecticut Drawing. Filed Oct. 30, 1958, Ser. No. 779,587

Cl im 1 -2 This invent-ion relates to bridgehead nitrogen com pounds. In one specific aspect, it relates to derivatives or lupine alkaloids which may be called lupine hydraziniurn compounds. This application is a continuation-in part of my co-pending application serial No. 547,831, filed November 18, 1955, now US. Patent No; 2,89 1,0601 A bridgehead nitrogen compound is an organic com- United 1 States PatentO pound, the molecular structure of which contains at least two mutually fused rings sharing a common nitrogen atom (the bridgehead nitrogen) and at least one other atom. The lupine alkaloids contain such a structure and actually contain this system twice. lupine hydrazinium compounds. display -remarka'bleand unexpected local anesthetic properties. 1

It is. therefore, an object of the p sen i ven i o provide a new class of pharmacologically useful compm l v v,

The compounds of my invention are prepared the ac-Y f? It has been discovered that V t e ofsh ne on he appropr a e. bnidseheadnitrosm compound. In the preferred practice of my invention, the

reactant'amine dissolved in an unreactive solvent is egg; posed to a stream of gaseous .chloramine. Theresultant lupine hydrazinium chloride is isolated by conventional glompounds containing anions ry techniqu s! other than chloride are prepared by metathesis, starting V be introduced.

In accot-dance with the present invention, I have made available a new class of compounds having the general with the chloride and a compound containing the anion to.

In the above-formula, A represents two hydrogens or a carbonyl oxygen. X' is an anion bearing the charge n; n also represents the number of cations required to balance the nio charg j compound. poses, 'X must be a pharmaceutically acceptable a on. he p i ar attr te at st n anion. re, n tox y a msafibi i Qhstw se fls chqice is- 'of little consequence, since-the primary a t x tyotm ncye c mrsurfist s d s a s .catio V l g j s. a ed r ha nse ut s 't r The salts obtained b" variation of-the anion may in some cases spscial. advan a s d 0 luhil e f h e fizaaor, lack b'fobjectionab'le taste and the like, but'these considerations are all subsidiary to thcliaracteris'ticsof:

the cation which are independent of the character of the lice solutions of the amine salts with base and extract the free a pin h a s ve u h s h o o o m Ate: t eatrnentof the extract with a conventional drying agent, the solution is ready for chloramination. While chloramine is most advantageously prepared as a gaseous chloramineammonia mixture obtained from a generator constructed according to the teachings of Sisler et" al., 'U.S. Patent 2,710,248, other methods are equally adaptable for the purpose of the present invention. For instance, chloramine can be made by reacting chlorine with an excess of ammonia in carbon tetrachloride or similar halogenated hydrocarbon solvents under controlled conditions of mixing at low temperatures. Such a process is fully described in US. Patent 2,678,258 to John F. Haller. A 1 other ei fective procedure is that of Coleman et a1. fully de scribed in Inorganic Synthesegvol. 1,59 (1939). Alternatively, the chloramine can be formed in the presence of the amine as describedin'the copending application Serial No. 605,230 filed August 20, 1956 which teaches the reaction of chlorine -and a tertiary amine ini the pres- 1 v ence of excessjammonia. E or simplicity, when both the amine-and the product are soluble in the same inert solve'nt;e.g., chloroform," chloramine may be formed in's'itu by-this method right in the solution containing the reactant tertiary amine. Ingeneral, the choice of solvent is, I one of economy and simplicity; When preformed 011191 ramine isused and good absorption is requiredyfor'efli cient reaction, it has been found desirable to bubble chloramine through a long column of a solution compris- 111g the tertiary aminedissolvcd in relatively cheap, inert ,fiyii-l ilsfif salventfitis meant-a solvent,

; U derthe-condition of the reaction. Solvents whichservethis purpo e include hy rocarbon .e-g-; ptane, cyclohexane, benzenaxylene, and. the likeyethers, e.g., diethrl ether, jdiamylethen-dioxane and anisole; amides, e,g., dimethylformamide and dimethylaeetan'zide; halohydrocar-bons, es chloroform, carbon tetrachloride;

. trichloroethylene and chlorobenzenernitroaromatics, e.g-.,

ni z be zene- 'FQI pecial purposes;-wa-ter-and-other hy-w.

pro ress s. In. aqueous solution, however, 1t i usually! assa in-to: concentrate or to evaporate to ryness. in:

order to, isolate the product.

Another method ofvprepar-i-ng. the novel my inventionisthe reaction of hydroxylamine-o-s'ulfonic acid with tertiary amines which produces the hydrazinium sulfate corresponding tothe tertiary amine used. Pref:

erably the appropriategter tiary amine and hydroxylamine o-sulfonic acid are allowed to react orare heated together anion. Hence all matters ofX are consideredequiv alent for'the purpose of the present invention. Specific,

but non-limiting, variants of X are as follows: chloride, bromide, iodide, sulfate, bisulfate, acetate, salicylate, valerate, oleate, phenate, laurate, borate, benzoate, lactate nitrate, diglycollate, phosphate, phenylethylbarbiturate,

in the presence of an alcoholic solvent but excess amine oeothen u t mesclyen s mavr e se ;v 'Erem bou hcth 7 use. ofiya solventis; not required;superior-results a-relcbra tained with a solvent because of the extremely exothermic reaction that quite often results. A frequent I purification step is the'treatment' of the reaction mixture 7 with a basic substance such as sodium carbonate to rel move acidicconstituents from the product hydrazinium' if:

PatentedJuly 426,

XLSQlzWnts: ethyl alcohol;and'iellosolvernay' e u e When t gelreaction is conducted;izi anhydrcus3 olution, thenroduet-t oftenfiprecipitatesa as thegre ctiou sulfate which is essentially neutral and stable to the action 01. base. Further purification is eifected by standard laboratory techniques.

4 It is obvious that not allot the novel hydrazinium compounds of my invention are capable of being prepared directly as shown above. in order to provide the other useful salts of the present'invention, 'it is necessary to prepare the compounds containing anions other than chloride or sulfate by metathesis. Many of the anions described supra can be obtained by mixing aqueous solutions of the hydrazinium chloride with appropriate reagents. More often than not, the desired product precipitates directly as the reaction progresses. This is the case where the new salt being formed is less soluble or insoluble in water. Other metathetical approaches are available and the method selected depends on experimental convenience, costs of reagents and the differences in physical properties between the product and thestarting material to be utilized in their separation. Reaction of a hydrazinium halide with a soluble silver salt, such as silver nitrate, results in the precipitation of silver halide and the formation of the hydrazinium nitrate. In an analogous manner, treatment of the sulfate with a soluble barium salt results in the precipitation of barium sulfate and conversion to the anion of the barium salt. Quite often the appropriate reactants are heated together in the absence of a solvent and the product isolated by standard laboratory techniques. Another approach independent of the formation of an insoluble solid, is to react the halide with an excess of the desired anion as its acid; hydrogen halide is evolved as the new salt is formed. When it is necessary to prepare a very soluble salt, the reaction of the hydrazinium hydroxide with equivalent amounts ofthe appropriate acid may be utilized; this approach is also used for the preparation of very pure compounds. (subjecting a hydrazinium'halide to-the action of moist silver oxide will give the hydraziniurn hydroxide) Amines suitable as starting materials to synthesize the Example I Sparteine sulfate pentahydrate (83 g.) was dissolved in 100 ml. of water. After excess sodium' bicarbonate had been added the amine base (theoretical Weight 46 g.) was recovered by ten extractions of the aqueous solution with lOO mI. portions of chloroform. The combined extracts were dried over anhydrous magnesium sulfate before being treated with achloramine gas'steam generated according to the teachings of Sisler et all as discussed above. After the reaction mixture had been filtered from the resultant ammonium chloride,-the filtrate was evaporated to dryness. The solid residue was washed first with. ether and then with hot ethyl acetate. A second washing with the hot ester gave 24- g. of N-aminolupinidinium chloride as pale yellow hygroscopic crystals melting ca. 94 C. Analytical data was consistent with the following formula:

Examples II and Ill Separate portions'of the crude chloride of the previous example were dissolved in water and treated with aqueous potassium hexafluorophosphate and with saturated aqueous picric acid. The resultant precipitates were collected by filtration and dried to give N-aminolupinidinium hexafluorophosphate (M.P. 57-58 C.) and N-aminolupinidinium picrate (M.P. 65-68" C.) respectively.

Example IV Local anesthetic activity was investigated in a manner similar to that of Luduena, Hoppe, Tainter, and Wessinger of the Sterling-Winthrop Institute. The backs of white guinea pigs were closely clipped and the test materials were injected intracutaneously into the clipped-skin area. Dilutions of the test compounds were prepared in physiological saline and four pigs were used per each dilution. A volume of 0.25 ml. of each test solution was injected in parallel rows on each side of the midline and the resulting wheals were marked for future identification. In order to minimize any bias that might be caused by differences in sensitivity between frontal and caudal areas, the injection sites for any one dilution of compound were alternated among the four pigs. The wheals were tested five minutes after injection and every five minutes thereafter for 30 minutes. At each test, the wheals were stimulated by a series of six pin pricks. The number of pricks that failed to evoke a reflex, skin twitch, or phonation by the animals were counted for each test. The maximum test scope for complete anesthesia which con tinued for 30 minutes would thus be 36. The results with a 1:125 dilution of N-aminolupinidinium chloride are tabulated below together with the physiological saline control.

' Time in Minutes Solution Guinea Average pig no. r 5 1o 15 20 25 30 total l ttttt i 1 Tm 3 o 0 0 o 0 2 2 I 4 o s 2 5 5 3 1s s s 2 7 9 1 a4 8.5 *i8888888 cmtml a o 0 0 0 o o 0 4 0 o 0 0 0 0 0 I claim:

1. New chemical compoun ds having the general formula:

wherein A is selected from the group, consisting of O and chloride:

4. As a new chemical compound, N-aminolupinidinium picrate.

5. As a new chemical compound, N-aminolupinidinium hexafiuoro-phosphate. a 7

No references cited. 

1. NEW CHEMICAL COMPOUNDS HAVING THE GENERAL FORMULA: 